Non-medullary thyroid cancer (TCA), the most common type of endocrine malignancy, accounts for most deaths due to endocrine cancers. Although the majority of TCAs are successfully managed with surgery and radioactive iodine (I-131) therapy (i.e. ablation of normal thyroidal postoperative "remnant" and treatment of metastases), the mortality associated with this disease has remained stable over the years, because these therapies are not effective for "clinically aggressive" tumors. The latter group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs, which show accelerated patterns of growth and/or fail to trap iodine efficiently. The loss of iodine concentrating ability by the malignant thyrocytes may be correlated with other cellular and molecular events that accompany de-differentiation. Our goal is to study the molecular events accompanying the natural history of clinically aggressive TCAs and the response of various molecular markers to standard therapeutic intervention(s), as well as investigate the feasibility of new therapies in pilot clinical trials through translational clinical research. Preoperative diagnostic methods include aspiration cytology (fine needle), tissue core surgical biopsy, neck ultrasonography and other conventional radiographic imaging, whole body scanning with I-131 or I-123 -as well as other radionuclides -, and suppression therapy trial with L- thyroxine. Specific aims of this study include: (i) optimization of methods of diagnostic imaging in TCA (especially using non-RAI-based radionuclides, such as 111In-octreotide and 18F-fluorodeoxyglucose positron emmission tomography) and serum thyroglobulin (Tg) measurement to diagnose residual/recurrent metastatic disease, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio (such as whole body and blood dosimetry and lesional dosimetry), (iii) PCR-based detection and quantification of thyroid-specific tumoral mRNAs (e.g. thyroglobulin mRNA and mRNAs for other tumor markers) in thyrocytes circulating in peripheral blood, (iv) analysis of mutations in genes involved in TCA growth, apoptosis, and mitotic cycle regulation, such as the thyrotropin receptor (TSHR), ras, p53, Fas/Fas ligand, ret/PTC, p53, mib1 and PCNA in primary and metastatic thyroid tumors, and, finally, (v) establishment of immortalized cell lines from human TCAs for in vitro studies. The relationship between the level of expression of markers of differentiation, as well as mutations in growth-relevant genes, and the clinical behavior of TCA will help further define the pathways responsible for thyrocyte growth and differentiation. Over the last year, we have expanded on our review of 3 decades of NIH (single institution) experience in 32 patients who underwent extensive secondary surgical resections of distant and locoregional metastases in an attempt to better define the role of aggressive metastatectomies in the multimodality management of patients with TCA. Additionally, in collaboration with our colleagues from the NCI, we are currently preparing a Phase II clinical trial investigating the effects of a novel, low-toxicity histone deacetylase inhibitor with pro-differentiating properties, i.e. depsipeptide, in the induction of differentiation (i.e. expression of Tg and NIS mRNAs), and tumoricidal activity in patients with TCA unresponsive to standard treatment methods. The desired therepeutic effect would be the induction/re-emergence of previously inexistent or the increase in currently insufficient iodine accumulation by the tumor, and thus the ability to render such tumors yet again manageable by 131-I. We are also planning to investigate the role of paclitaxel as a radiosensitizing agent in a pilot clinical trial in conjunction with either conventional radiotherapy or intensity-modulated radiotherapy (IMRT) in patients with locally advanced metastatic disease in the neck and upper mediastinum, which threatens vital neck structures and currently has no effective treatment options.